Administration of drugs to the gastrointestinal tract is a preferred method for both human and veterinary medicine. Most conventional drugs are well absorbed from the intestines, usually by a process of passive diffusion, although certain compounds are taken up by more specific mechanisms such as facilitated or active transport. Polar molecules such as cimetidine, ranitidine, sodium cromoglycate bisphosphonates (such as clodronate) and captopril often display poor or erratic absorption when dosed orally. The polypeptide and polysaccharide drugs such as insulin, calcitonin, parathyroid hormone or fractions or analogues thereof, luteinising hormone releasing hormone (LHRH) or analogues thereof (eg. nafarelin, buserelin, goserelin), growth hormone, growth hormone releasing hormones, colony stimulating factors, erythropoietin. somatostatin, interferons and heparins cannot be given orally because, not only are they poorly absorbed because of their polar nature and size, but they can also be degraded by the endogenous enzymes present in the gastrointestinal tract. If such drugs are given orally the absolute bioavailability (defined as the quantity reaching the systemic circulation) as compared to parenteral administration is generally low (less than 1%). Cyclosporin, a polypeptide, is a notable exception. It is non-polar in nature and has a partition coefficient (octanol/water) of more than 1000. This drug is quite well absorbed from the gastrointestinal tract.
Despite the inherent problems in attempting to administer polar drugs orally, various attempts have been made to improve oral absorption. Strategies have included chemical modification to stabilise the drug and/or make it more lipid soluble and hence improve its chances to diffuse across the lipid membrane or the gastrointestinal tract. Other workers have added stabilising agents such as peptidase inhibitors (eg. aprotinin) to reduce metabolic loss, while others have used various absorption promoting agents in the form of non-ionic surface active agents, bile salts and analogues thereof, phospholipids, chelating agents or acyl carnitine. These previous attempts have been well reviewed in the relevant literature.
For example the various means to enhance the intestinal permeability of proteins, peptides and other polar drugs have been reviewed by Swenson and Curatolo (Advan. Drug Del. Rev. 8, 39, 1992). While mixed systems were reported these were restricted to systems comprising bile salt/oleic acid mixtures and polyethoxylated hydrogenated castor oil/oleic acid mixtures. The ileocolonic delivery of insulin at 10 units/kg to the dog using a mixed micelle system comprising sodium glycocholate (30 mM) and a fatty acid (linoleic acid) of 40 mM has been described by Scott-Moncrieff and others, J. Pharm. Sci. 83, 1465 (1994). The reported bioavailability was 1.4%. Medium chain glycerides (MCGs) have been reported to enhance the intestinal absorption of hydrophilic drugs. For example Beskid et al. (Pharmacology, 34,. 77, 1988) reported that a formulation incorporating a mixture of glyceryl mono- and di-caprylate enhanced the absorption of an antibiotic from the intestinal tract of rats. Mixtures of medium chain glycerides with medium chain length fatty acids (C.sub.8 -C.sub.12) have also been reported (see for example Muranushi et al. Chem. Phys. Lipids 28, 269, 1981).
It has been known for some time that sodium caprate can act as an absorption promoting agent, probably by the perturbation of membranes or modification of tight junctions between cells (Kajii et al. J. Pharm. Sci. 77 390, 1988). The absorption promoting effect of fatty acids has also been associated with the chelating ability for calcium ions and an inhibiting action on leucine amino peptidase activity (Mishima et al. J. Pharmaco. Biodyn. 10 624, 1987). The effect of fatty acids and their derivatives on the intestinal absorption of insulin in rat has been reported by Muranishi et al (Drug Devel. Ind. Pharm. 19 929, 1993). A critical carbon chain length (C.sub.10) was seen with the fatty acids.
Morishita et al (Biol. Pharm. Bull. 16 68, 1993) explained different sites for the absorption of insulin from the rat intestine. They employed sodium caprate and sodium glycocholate as absorption enhancers. They concluded that the ileum was the most preferred site for insulin absorption while the colon had a greater sensitivity to the effect of the selected absorption enhancers.
The use of polyglycolysed glycerides (Labrasol) to increase the absorption of insulin has been described in European Patent No. 0351651. Formulations were prepared based on a mixture of insulin (as an aqueous solution) and LABRASOL.TM.. Formulations were administered intraduodenally to rats (approx. 250 g) at an insulin dose of 5-20 IU/rat and a LABRASOL.TM. dose of 12.5-50 mg/rat. The formulations were administered to dogs as either an intraduodenal infusion or in an enteric coated capsule at approx. 12 IU/kg insulin and a high level of LABRASOL.TM. (80-90 mg/kg). Dogs were also administered the formulations by the buccal route at 10 IU/kg insulin and 17 mg/kg LABRASOL.TM..
EP 0418674 discloses antibiotic formulations based on either LABRASOL.TM.+caprylic acid or LABRASOL.TM.+caprylic acid+sodium caprylate. They were administered orally or rectally to animals. Orally, no drug was absorbed from the control formulation, whereas the formulations containing enhancers LABRASOL.TM./caprylic acid or LABRASOL.TM./caprylic acid/Na caprylate resulted in absorption of drug. Formulations containing the enhancers were also effective when administered rectally. The formulations were not targeted to the colon. Indeed it is well appreciated by those skilled in the art that it is inappropriate to administer antibiotics into the colonic region because of the effects on the local flora and the induction of severe clinical conditions such as pseudomembranous colitis.
WO 94/08622 describes a pharmaceutical composition containing calcitonin and a polyglycolipid glyceride to promote drug absorption that could be delivered by a variety of different routes to include mucosal surfaces. The composition was stated to have a pH of 3-5.7.
It is now appreciated that animal models may not be well predictive of man in terms of absorption from the gastrointestinal tract and moreover that cell cultures (eg. CaCo-2 confluent cell monolayers) and gut loops do not properly reflect the in vivo situation where mucus, enzymes and gastrointestinal mobility and transit can have a major influence. Davis (I. Pharm. Pharmacol. 44 Suppl. 1 186, 1992) has described these problems in detail.
Factors to be considered in the administration of polar molecules orally so as to obtain a systemic effect can be summarised as follows. The chosen materials for absorption enhancement should be approved for administration by the oral route; the chosen agent should give rise to a sufficient increase in drug absorption without apparent side effects; the final formulation should conserve the stability of the drug and be in the form of an easily administered product such as a tablet or capsule.